Chances of PREP failing?

[wood]

HIV2 less aggressive and much less common. I have found no studies about Truvada and HIV2 - and don't know if there is an active study or planned not. What I do read suggests that Truvada would probably be effective, but until this is studied, the only valid statement is "I don't know". As a guy on PrEP I am not terribly worried... In the synopsis of studies I've read TasP for HIV2 has also not been studied. Poz1956 and Bearbandit might have better access to details about HV2...

It is always a good idea to talk with your sex partners and get to know them.

You are right that HIV2 seems to be less aggressive. But it always makes sense to be reasonably careful.

One reason I am a bit curious is that I am thinking about taking a trip to south africa and I know HIV2 is somewhat more common there. While I am there, lets just say I plan on soaking up A LOT of the culture on my trip.

[bearbandit]

Fascinating thread guys (though I'd rather read porn - had to turn down an opportunity to critique a friend's new book this week because I just wasn't up to it - and I want to read that book!)

Maraviroc is being studied as the next step in PrEP, basically it's an entry inhibitor, stops HIV ever getting into your CD4 cells. From what I understand, maraviroc would give the same effect as having two copies of the CCR5 gene, which basically make you invulnerable to HIV because it has no way to access those t-cells it loves so dearly. I know a couple of guys who've had the whole genetic assay thing done and both have turned up with double CCR5 chromosomes. One's an escort who always works safe, not because of of HIV but because of other STIs around. He's a good enough fuck that you actually forget the condom's there... The other is the partner of a guy whose been HIV+ for seventeen years. Never used a condom that I know of, and if they did it was for kink.

If maraviroc works out as PrEP we're looking at a major step forward. The whole point of PrEP is to catch the little fucker while it's relatively isolated, as it is when trying to set up camp in someone's body and smash the little fucker to bits. The more drugs we have available to us for PrEP, the more we can start matching them to body type and so on (does a straight woman weighing #110 need as much as a bear weighing in at #220?)

Edited April 16, 2014 by bearbandit
forgotten close parenthesis

[Guest JizzDumpWI]

I'm glad progress continues... I tend to agree with RT that dosing is still over the top - but I'm not willing to mess with dosing. Then to being uncut and bottom much more than topping, my apparent risk is higher.

[Poz1956]

Maraviroc is being studied as the next step in PrEP, basically it's an entry inhibitor, stops HIV ever getting into your CD4 cells. From what I understand, maraviroc would give the same effect as having two copies of the CCR5 gene, which basically make you invulnerable to HIV because it has no way to access those t-cells it loves so dearly.

Just a minor couple of corrections Bear. Gosh but we're getting into Deep Geek here. Who'd have thought a forum on "natural sex" would contain so much science.

These days, we tend to call the cell that HIV reproduces inside, a CD4 cell. I remember "way back when" they used to be called T4 cells, or Helper T cells. (Long version: CD4+ T Lymphocyte) Technically CD4 is a protein on the surface of that cell and the primary attachment point for HIV. (Other cells have the CD4 protein as well. HIV tends to hitch a ride on, or hide inside those other cells, but doesn't reproduce in them.)

CCR5 is another protein on the surface of the T4. We all have CCR5. It is a co-receptor of HIV. GP120 on HIV undergoes a structural change, after it attaches to CD4, which allows it to also connect with either CCR5 or CXCR4. Viruses using CCR5 are the predominant species found during the early stages of viral infection, suggesting they may have a selective advantage during transmission and/or the during the acute phase of infection. That fact probably makes it an excellent target for PrEP.

The CCR5 Delta 32 genetic mutation, changes the shape of CCR5 enough that HIV can't attache to it. Most long term non-progressors have one copy of that gene, meaning that some of their CCR5 receptors on T4 are misshapen. Those immune to HIV received the Delta 32 mutation from both parents, and all of their CCR5 co-receptors cannot match up with GP120 on HIV.

Maraviroc (Selzentry, Celsentri) is the mirror image of normal CCR5. (If you thought like two pieces of a jigsaw puzzle, you'd get the right idea) That is, Maraviroc while free floating in the blood, binds to the CCR5 protein on the T4 cells. HIV could still attach to CD4, but because CCR5 is already occupied, it can't mate up with the co-receptor. Therefore HIV cannot fuse with the T4, and "inject" its contents, as the first step in reproduction.

HIV could still mate with both CD4 and CXCR4, allowing it entry into the T4, but it tends to be during the late stages of infection that HIV variants capable of attaching to CXCR4 are produced. At least half of all Pozzies harbour only CCR5-using viruses throughout the entire course of infection. (God the stuff I learn while fact checking what I write.) Apparently chronic exposure to THC increases the expression of CXCR4 on both CD4 and CD8 cells. I wonder if that means heavy use of pot in late stage HIV would be a bad idea? I suppose at that point, the analgesic effects outweigh the potential for disease progression.

Before HIV, doctors didn't know very much about how the immune system functioned. It took the great death in the 80's, and the loud voices of Act-Up (and others) to spark the research. They still don't know it all. There is some concern about blocking CCR5 over the long term, because scientists don't fully understand how it's normally used in our bodies. We know that those with the Delta 32 mutation have a higher susceptibility to the West Nile Virus. I wonder if that explains why Delta 32 is so rare in Africa?

Now having re-read all of this, I have a craving for Alphabet Soup!!

[rawfuckr]

There is some concern about blocking CCR5 over the long term, because scientists don't fully understand how it's normally used in our bodies. We know that those with the Delta 32 mutation have a higher susceptibility to the West Nile Virus. I wonder if that explains why Delta 32 is so rare in Africa?

Hey Poz1956, enjoying your posts. The way I understood it CCR5 delta 32 knocks the whole CCR5 gene down making it useless. People who are homozygous for it (those who have two copies) have effectively no CCR5 protein on the cell surface and therefore no chance for HIV to bind to it. The amazing part of it is that all the folks with two copies, around 2% of europeans seems to have perfectly normal lives, so you'd think there should be no consequence about blocking it with Maraviroc or other drugs on those people who have normal CCR5.

For those folks who are interested 23andme.com will check your CCR5 status. If you have the two copies, luckily for you, you will likely never get HIV.

[bearbandit]

Poz1956 - I love your posts (and corrections where I get it a bit wrong). I learn more from them than the charity I volunteer for.

Jizz - we have to look at dosing at some point soon: I blame my diabetes on overdosing on ritonavir (I was warned beforehand, but in those days it was keep me alive till tomorrow, I'll worry about the other shit later). (un)fortunately the other shit came: I'm pretty sure I'm the longest term survivor in Wales and amongst the top ten in the UK. Some days I wonder if it was worth it, and the irony is that when I got it we didn't even know there was a virus out there.

[Poz1956]

Hey Poz1956, enjoying your posts. The way I understood it CCR5 delta 32 knocks the whole CCR5 gene down making it useless.

I guess we're both party right.

The CCR5-delta32 mutation results in a smaller protein that isn't on the outside of the cell anymore.

There's also another fusion inhibitor in the works that instead of binding to CC5, it mates with HIV itself. Same sort of puzzle piece/mirror image/lock and key analogy. It blocks up HIV's ability to mate with CD4 cells.

[rawfuckr]

I guess we're both party right.

The CCR5-delta32 mutation results in a smaller protein that isn't on the outside of the cell anymore.

There's also another fusion inhibitor in the works that instead of binding to CC5, it mates with HIV itself. Same sort of puzzle piece/mirror image/lock and key analogy. It blocks up HIV's ability to mate with CD4 cells.

Interesting. So CCR5 delta 32 is essentially a different gene producing a different protein. What is the name of that new fuison inhibitor that acts directly on HIV?

[Poz1956]

Like Neo, we're taking the Red Pill, and going further down the rabbit hole, to even deeper geekdom. ++1

The CCR5 gene, that encodes the CCR5 protein, is located on the short (p) arm of chromosome 3, at position 21.

People with the Delta 32 mutation are Missing part of that gene. The "Delta" in this case means deleted.

Now we get voyeuristic, and observe the mating rituals of HIV. (Keep your hands inside the ride at all times. If needed, you will find air sickness bags tucked into the seat pocket ahead of you.)

GP120 is a protein on the surface of HIV. When GP120 binds with the CD4 receptor, it causes that protein to change shape. (Think "uncoil" - my words, but an effective image) That shape change allows GP120 to bind with CCR5. If the virus has the ability to connect with CXCR4 that connection point is revealed by the change. The morphing also exposes the previously hidden GP41.

GP41 is another protein on HIV. After GP120 binds with both CD4 and CCR5, GP41 causes the shell to fuse with the T4, allowing the viral contents to enter the cell. Drugs that bind with that protein are called Fusion Inhibitors.

Enfuvirtide (Fuzeon) is currently approved and in use.

There several a points where we could inhibit HIV's entry. On the viral shell, there is more than one positions to attack on GP120, as well as GP41. On the T4 both CD4, & CCR5 are good targets. There are a number of agents being studied that can interact with those proteins and inhibit HIV's use of the T4. Studies into a compound that inhibits the interaction between the virus and CXCR5 were halted, as they showed very little antiretroviral activity. (That makes sense since half of those with HIV have a variant that ONLY binds with CCR5.)

Owe. My head hurts. You guys are making me read more and learn stuff. I need a cocktail. Or I just need some cock. Maybe what I really need is some tail. Lets make it a real fun night and have all three.

-----

++1: It's a reference to a key scene in "The Matrix." If Neo takes the Blue Pill, he stays in the manufactured reality of the Matrix. But since Neo takes the Red Pill, he is located, unplugged from the Matrix, and shown the real world.